All United States patents and patent applications referred to herein are hereby incorporated by reference in their entireties into the present application. In particular, U.S. Pat. Nos. 6,337,350, 6,589,944, 6,605,642, and 6,787,566, 7,320,988, and U.S. Patent Application Publication 2007/0117819A1 (U.S. application Ser. No. 11/594,981), which refer to various compounds, including LR-90 and LR-102, processes for their preparation, and their uses, are hereby incorporated by reference in their entireties. Moreover, throughout this application, various publications are referenced, which, along with the above-referenced patents and applications, illuminate the background of the invention or provide additional details respecting the practice. These publications also are hereby incorporated by reference in their entireties into the present application. Full bibliographic citations for the publications can be found listed immediately preceding the claims. In the case of conflict between any of the incorporated references and the present specification, the present specification, including definitions, will control.
Glucose and other reducing sugars react and bind covalently to proteins, lipoproteins and DNA by a process known as non-enzymatic glycation. Glucose latches onto tissue proteins by coupling its carbonyl group to a side-chain amino group such as that found on lysine. Over time, these adducts form structures called advanced glycation endproducts (AGEs) (protein-aging). These cross-linked proteins stiffen connective tissue and can lead to tissue damage in the kidney, retina, vascular wall and nerves.
In human diabetic patients and in animal models of diabetes, these non-enzymatic reactions are accelerated and cause accumulation of AGEs on long-lived structural proteins, such as collagen, fibronectin, tubulin, lens crytallin, myelin, laminin and actin, in addition to hemoglobin, albumin, LDL-associated proteins and apoprotein. The structural and functional integrity of the affected molecules, which often play major roles in cellular functions, are perturbed by such modifications, with severe consequences on organs such as kidney, eye, nerve, and micro-vascular functions (as noted above). This consequently leads to various diabetic complications, including nephropathy, atherosclerosis, microangiopathy, neuropathy and retinopathy. Boel et al., J. Diabetes Complications 9:104-129, 1995; Hendrick et al., Diabetologia 43:312-320, 2000; Vlassara and Palace, J. Intern. Med. 251:87-101, 2002. AGEs thus have been implicated in the pathogenesis of a variety of debilitating diseases such as diabetes, atherosclerosis, Alzheimer's and rheumatoid arthritis, as well as in the normal aging process. Most recent researchers confirm a significant role of the accumulation of AGE cross-links in promoting the decreased cardiovascular compliance of aging (Asif et al., 2000).
In recent years, several promising therapeutic drugs that could inhibit or break the AGE crosslinks in tissues and cells, and thus prevent their consequences, have been reported. Both inhibitors of AGE formation and AGE-breakers not only may have a beneficial effect in reducing complications of AGE-related diseases, AGE-breakers may cure the disease by removing AGEs from damaged tissues and cells. U.S. Pat. No. 6,787,566, (and other patents incorporated by reference herein) describes several compounds that have been found to be active in breaking AGE-protein cross-links, including methylene bis[4,4′-(2-chlorophenylureidophenoxyisobutyric acid)] (“LR-90”) and 1,4-benzene-bis[4-methyleneaminophenoxyisobutyric acid] (“LR-102”).
Diabetic nephropathy is one of the most serious complications of diabetes and its incidence is increasing dramatically worldwide. It is now the leading cause of end-stage renal failure and the requirement for chronic dialysis or renal replacement therapy [1, 2]. The characteristic features of diabetic nephropathy include persistent albuminuria, a progressive decline in renal function and, histopathologically, mesangial expansion followed by glomerulosclerosis and interstitial fibrosis [3, 4]. Although the pathological and clinical indices of diabetic nephropathy are well described, the precise molecular mechanisms underlying its pathogenesis are not completely understood. Over the last decade, evidence has accumulated, implicating AGE and AGE-protein crosslinking as a major factor in the progression of diabetic nephropathy [5, 6]. Several studies have shown that the extent of AGE formation, particularly AGE adducts in glomerular and tubulointerstitial compartments, correlates with the severity of diabetic nephropathy [7, 8]. AGE may contribute to diabetic tissue injury by a number of different pathways, including receptor-independent alterations of the extracellular matrix (ECM) architecture and protein cross-linking, as well as by modulating expression of various inflammatory genes, cytokines and growth factors through cell surface receptors, including the receptor for AGE (AGER) [9, 10]. Previous studies have shown that LR-90 prevented the development of experimental type 1 diabetic nephropathy. (24).
Prospective studies of the natural history of type 2 diabetes have shown that the prediabetic state is characterized by resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia. The transition from pre-diabetes to Type 2 diabetes occurs when the secretory capacity of the pancreatic d cell is no longer able to compensate for the insulin resistance. Resistance to insulin action is a common abnormality present in major human diseases such as diabetes mellitus and obesity. Abdominal obesity contributes to insulin resistance, a metabolic abnormality linked to the development of type 2 diabetes and cardiovascular disease. Insulin resistance generally precedes the development of type 2 diabetes. Currently, an estimated 20.5 million US adults have diabetes and another 54 million have impaired glucose tolerance, an intermediate step between insulin resistance and diabetes.
Accordingly, there currently exists a need in the art for methods of ameliorating or inhibiting insulin resistance in a subject, particularly a subject who has type 2 diabetes or is in a prediabetic state. There is also a need for prevention of the development of type 2 diabetes and type 2 diabetic nephropathy, including those instances in which multiple risk factors, such as hyperglycemia, dyslipidemia, obesity, insulin resistance, or hypertension, contribute to renal injury.